Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of
developing Alzheimer's disease (AD). This review briefly describes current concepts
in mechanisms linking DM and insulin resistance/deficiency to AD.
Insulin/insulin-like growth factor (IGF) resistance can contribute to
neurodegeneration by several mechanisms which involve: energy and metabolism
deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic
reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with
increased production of neuro-inflammation and activation of pro-apoptosis cascade.
Impairment in insulin receptor function and increased expression and activation of
insulin-degrading enzyme (IDE) have also been described. These processes compromise
neuronal and glial function, with a reduction in neurotransmitter homeostasis.
Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or
insoluble larger aggregated fibrils in the form of plaques that are neurotoxic.
Additionally, there is production and accumulation of hyper-phosphorylated insoluble
fibrillar tau which can exacerbate cytoskeletal collapse and synaptic
disconnection.

Population aging is a global phenomenon leading to an increase in chronic diseases such
as dementia and diabetes mellitus (DM), which pose an epidemic challenge to global
health care systems. In 2012, the WHO published that 35.6 million people had dementia
worldwide and that this number is set to reach 65.7 million by 2030.1 Alzheimer's disease (AD) is the most common cause
of dementia, especially in the elderly population.1 Recently, the International Diabetes Federation2 estimated that 382 million people had diabetes in 2013, where this
number may rise to 592 million within less than 25 years.2 Moreover, 80% of the total number affected live in low- and middle-income
countries and Type 2 diabetes (T2DM) is the most common type of DM.2 The prevalence of AD and T2DM increases with aging.3

The AD pathology is characterized by the accumulation of the following in the brain:
amyloid beta precursor protein (AβPP)-Aβ large insoluble fibrillar aggregates in the
form of plaques, soluble neurotoxic oligomeric fibrils, hyper-phosphorylation of tau
protein with neurofibrillary tangles (NFTs) deposition, dystrophic neuritis, and
neuropil threads.4,5 In familial forms of AD, the mutations in AβPP,
presenilin 1 (PS1) and 2 (PS2) genes, or inheritance of the Apolipoprotein E e4
(ApoE-e4) allele can cause increased synthesis and deposition of AβPP- Aβ.6,7 However, the cause of AβPP-Aβ accumulation in
sporadic AD, the most common form of the disease, remains unknown.5 However, evidence suggests that impairment in insulin and
insulin-like growth factor (IGF) compromises AβPP expression and protein processing
which could be responsible for AβPP-Aβ accumulation.8

The association between DM and AD is controversial in literature.9,10 Many studies have demonstrated a positive
association between DM and AD, especially in epidemiological research, studies in
animals and cells,11-17 but these findings have not been entirely
confirmed in neuropathological studies.3,18-23 Based on this positive association,
researchers have studied DM treatments as a target to diminish or avoid AD onset and
progression.24-28

The exact mechanisms by which DM affects the brain remain unclear, but this probably
occurs through cerebrovascular and neurodegenerative changes.29 The aim of this article was to provide a brief review on the main
mechanisms associating AD with DM due to insulin resistance and deficiency.

Insulin and insulin-like growth factor actions in the central nervous system.
The insulin produced by the pancreas can cross the blood brain barrier (BBB) from
the circulation to the brain by a receptor-dependent mechanism,30 but the levels of insulin expression in the brain are modest
compared to circulating levels.10 The transport
of peripheral insulin across the BBB and the consequences of peripheral hyperinsulinemia
or hypoinsulinemia are significantly important to cerebral insulin signaling.10 Insulin binding activity has been identified in
the brain in a number of species, including humans.31,32 Furthermore, insulin receptors (IR) are
expressed in cerebral vasculature and can mediate insulin traffic across the BBB.33

Insulin and IGF play an important role in brain function and structure.5 Insulin, IGF-1 and IGF-2 polypeptides and receptor
genes are expressed in neurons34 and glia,35,36 particularly in structures that are targeted
in neurodegenerative diseases.34,35,37 IGF and insulin are associated with regulating
and maintaining cognitive function,38 and
participate in neuronal and glial functions such as growth, metabolism, survival, gene
expression, protein synthesis, cytoskeletal assembly, neurotransmitter function, synapse
formation and plasticity.34,39

Glucose transporter 4 (GLUT4) is very important for glucose uptake and utilization in
the brain.38 Insulin stimulates GLUT4 gene
expression and protein trafficking from the cytosol to the plasma membrane, modulating
glucose uptake and utilization.38 Consequently,
the regulation of neuronal metabolism and the generation of energy needed for cognition
and memory are linked to insulin stimulation of GLUT4.38 GLUT4 is abundantly expressed along with insulin receptors, in medial
temporal lobe structures which are affected in AD pathology. Nevertheless, post-mortem
brain studies have not detected significant reductions in GLUT4 expression in AD.40 Deficits in brain glucose utilization and energy
metabolism, and brain insulin/IGF resistance could be mediated by impairments in GLUT4
trafficking between the cytosol and plasma membrane.38

Insulin and IGF binding to their own receptors activates some pathways, leading to
phosphorylation and activation of intrinsic receptor tyrosine kinases. The
phosphorylated receptors interact with IR substrate molecules and promote transmission
of downstream signals that stimulate growth, survival, metabolism, plasticity and
inhibit apoptosis.38

Brain insulin/IGF resistance and AD. AD has been associated with deficits
in insulin/IGF signaling due to the effects of insulin/IGF resistance and
deficiency.5 Deficits in cerebral glucose
utilization have been described in the early stages of AD.41-44 Suzanne de la Monte and colleagues have
proposed the concept of AD as "Type 3 diabetes".40 They observed an inverse correlation between IR abundance and the Braak
score of AD brains, with 80% reduced IR substrates levels in the most severe cases. They
described reduced messenger RNA levels of IGF-1 and increased Tau protein levels
regulated by IR.40,45 Studies with small interfering RNA molecules
showed that molecular disruption of brain insulin and IGF receptors was sufficient to
cause cognitive impairment and hippocampal degeneration similar to AD molecular
abnormalities.46

Brain insulin/IGF resistance/deficiency can appear independently of Type 1 and Type 2
diabetes.5 Neurodegeneration can occur by
several mechanisms such as the activation of kinases that aberrantly phosphorylate tau,
the expression of AβPP and accumulation of AβPP-Aβ in brain insulin/IGF resistance.38 Hyperglycemia leads to the accumulation of
advanced glycation end products (AGEs) that disrupts removal of Aβ42 and induces Aβ and
Tau glycation, promoting Aβ aggregation and NFTs formation in the brain.38,47,48 AGE production is found in normal aging, but
becomes highly accelerated in diabetes.49 Recent
evidence suggests that glyceraldehyde-derived AGEs (glycer-AGE) are the predominant
modification of the most toxic forms of AGEs, and Glycer-AGE-modified proteins are
directly toxic to cultured neurons. Diabetic serum enriched with glycer-AGE modified
proteins has shown toxic effects on neurons.10
AGEs are also linked to microvascular alterations in hyperglycemia and diabetes.50 Receptor for advanced glycation end products
(RAGE) expression has been associated with pathological conditions such as diabetic
vascular disease, chronic inflammation and AD.51,52 Studies with immunohistochemistry for RAGE in
AD brains have demonstrated that RAGE increased expression in neurons, microglia,
astrocytes and vascular endothelial cells.53,54 RAGE binds and interacts with AGEs and also
with Aβ.49 RAGE interaction with AGE-modified
proteins in either diabetes or AD, or Aβ in AD, can produce damaging inflammatory
responses55,56 and be responsible for vascular complications
in DM and AD.57-59 RAGE mediates the transport of plasma Aβ
across the BBB60 and the migration of monocytes
across the human brain endothelial cells in response to Aβ.61

Microvascular disease is seen as a consequence of diabetes and can also be found in AD
brains, possibly contributing to the cognitive impairment and neurodegeneration seen in
AD.5,62 Decreased blood flow and impairment of oxygen
and nutrient delivery exacerbate the adverse effects of insulin/IGF resistance.63 Consequently, there is an increase in oxidative
stress and activation of signaling mechanisms which promote aberrant tau
phosphorylation, AβPP cleavage, AβPP-Aβ deposition, and mitochondrial dysfunction.38,63

The insulin-degrading enzyme (IDE) has the property of catabolizing insulin and Aβ, and
may play a critical role in Aβ clearance in the brain as Aβ scavenger protease.68,69 IDE acts as a general regulator of amyloid
burden in the pancreas and brain.70 Insulin
regulates IDE expression and can directly compete with Aβ for binding to IDE.71 In hyper-insulin states, IDE can be diverted to
degrade insulin, consequently allowing AβPP-Aβ accumulation.70 Mutations in the IDE gene in mice resulted in reduced activity of
this enzyme, lower rates of Aβ and insulin degradation, additionally developing
hyperinsulinaemia and accumulating Aβ species in their brains.72 Chronic hyperglycaemia, hyperinsulinaemia, oxidative stress,
accumulation of AGEs, increased expression and activation of IDE, increased production
of pro-inflammatory cytokines, and cerebral microvascular disease associated with
peripheral insulin resistance could result in mild cognitive impairment and
neurodegeneration.38,73

Brain insulin/IGF resistance and Aβ pathology. Altered proteolysis with
increased AβPP gene expression results in the accumulation of 40 or 42 amino acid length
Aβ peptides that can aggregate and have been described in AD pathology. Dysregulated
expression and processing of AβPP leads to the accumulation of AβPP-Aβ oligomeric
fibrils or insoluble larger aggregated fibrils in the form of plaques that are
neurotoxic.5 The interest in the role of
impaired insulin/IGF signaling as either the cause or consequence of dysregulated
AβPP-Aβ expression and protein processing has grown in literature.38 Insulin can accelerate trafficking of AβPP-Aβ from the
trans-Golgi network to the plasma membrane as well as its extracellular secretion74 and also inhibits its intracellular degradation
by IDE.75 Impaired insulin signaling can disrupt
both the processing of AβPP and clearance of AβPP-Aβ.76 Simultaneously, AβPP-Aβ affects insulin signaling by competing with
insulin, or reducing the affinity of insulin for binding to its own receptor.77 AβPP-Aβ oligomers desensitize and reduce the
surface expression of IRs, consequently inhibiting neuronal insulin-signaling.67 Additionally, intracellular AβPP-Aβ interferes
with PI3k activation of Akt, leading to reduced signaling, increased activation of
GSK-3β, and hyper-phosphorylation of tau. Increased levels of GSK-3 promote AβPP
processing and AβPP-Aβ accumulation.78

Brain insulin/IGF resistance and Tau pathology. In AD, the main neuronal
cytoskeletal lesions correlated with severity of dementia, including NFTs and dystrophic
neurites, contain aggregated and ubiquitinated insoluble fibrillar tau.4,38,79 Tau gene expression and phosphorylation can be
regulated by insulin/IGF stimulation.80,81 Reduced insulin/IGF signaling can impair tau
gene expression and contribute to tau pathology.82 Brain insulin/IGF resistance results in decreased signaling through PI3K,
Akt,80,81 and Wnt/β-catenin,83 and increased activation of GSK-3β.84,85 The hyper-phosphorylation of tau, which leads
to tau misfolding and fibril aggregation in AD pathology, can be partly due to GSK-3β
overactivation.86 Tau hyper-phosphorylation is
mediated by increased activation of cyclin-dependent kinase 5 (cdk-5) and c-Abl
kinases,87,88 and inhibition of protein phosphatases 1 and
2A.88,89 Tau protein misfolds and self-aggregates into
insoluble fibrillar structures lead to neurofibrillary tangles, dystrophic neurites, and
neuropil threads.38,90 The results of generation and accumulation of
hyper-phosphorylated insoluble fibrillar tau are the exacerbation of cytoskeletal
collapse, neurite retraction, and synaptic disconnection.38Table 1 summarizes the main mechanisms linking
brain insulin/IGF resistance to AD pathology.

Conclusions. A body of evidence has shown that the structural and
functional integrity of the CNS can be compromised in the presence of brain insulin and
IGF resistance or deficiency. These changes can contribute to AD pathology and
conversely, AD pathology can enhance brain insulin and IGF resistance, functioning as a
positive feedback loop. However, it is necessary to bear in mind that the majority of
studies have been conducted in the experimental field with animal or cell models.
Elucidating the question of a connection among DM, brain insulin resistance/deficiency
and AD is very important, especially for planning novel strategies to prevent and treat
AD in the future.

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